Blindness is the medical condition of lacking visual perception for physiological or neurological reasons. As many as tens of millions of people, which accounts for 0.2-0.5% of the population of the world, are affected with blindness, and are suffering from great losses in personal, social and economical respects. Retinal photoreceptor degeneration is one of the more dominant etiologies of blindness, caused innately or by other various factors, including retinal dysplasia, retinal degeneration, aged macular degeneration, diabetic retinopathy, retinitis pigmentosa, congenital retinal dystrophy, Leber congenital amaurosis, retinal detachment, glaucoma, optic neuropathy, and trauma. No drugs have been developed for the fundamental treatment of these diseases thus far. To date, the replacement of dysfunctional photoreceptor cells, the alpha and omega of these retinal diseases, with new ones is regarded as the only promising therapy. Photoreceptor cell implantation is thought to prevent blindness or recover imperfect eyesight by delaying or restraining retinal degeneration, regenerating degenerated retina, and enhancing retinal functions.
Stem cells have become a candidate useful for cell therapy of retinal diseases including bone marrow stem cells (BMSC), cord blood stem cells, amniotic fluid stem cells, fat stem cells, retinal stem cells (RSC), embryonic stem cells (ESC), induced pluripotent stem cells (iPSC) and somatic cell nuclear transfer cells (SCNT).
No significant research results have been yet suggested regarding the differentiation of stem cells into retinal cells (particularly, photoreceptor cells) and cell therapy based thereon. The differentiation of these stem cells into retinal cells might make it possible 1) to guarantee an infinite cell source for efficient cell therapy, 2) to identify the differentiation mechanism from embryonic cells and retinal progenitors into retinal cells, which has remained unclear, 3) to find retina differentiation-related genes and molecules and lesions thereby, 4) to understand the pathogenesis of retinal degenerative diseases, and 5) to develop drugs for preventing retinal degeneration and protecting the retina.
Since the first establishment thereof, human embryonic stem cell lines have been suggested to have the ability to differentiate into various types of cells which are useful for the cellular therapy of various diseases. Human embryonic stem cells appear to have a high potential when it comes to allowing the accurate examination of pathogenetic mechanisms and supplying fresh cells that can substitute for dysfunctional cells in clinical treatment. The production of human ESC derived-retinal photoreceptor cells under a completely identified reproducible condition and the use thereof in transplantation would guarantee a highly potential and effective therapy for retinal photoreceptor cell-related diseases. It has been assumed that human ESC derived-cells will have the same properties and functions as did the cells formed that were formed through a normal differentiation processes. Based on this assumption, differentiation has been induced under circumstances similar to those of the developmental stages to produce pancreatic hormone-expressing endocrine cells (D'Amour, et al., Nat. Biotechnol., 2006; 24: 1392-401), neurons (Pankratz, et al., Stem Cells 2007; 25: 1511-20), muscle cells (Barberi et al., Nat. Med., 2007; 13: 642-8), and vascular endothelial cells (Wang, et al., Nat. Biotechnol., 2007; 25: 317-8). Also, many attempts have been made to differentiate human ESC into photoreceptor cells which may be effectively used to treat retinal diseases, but this ended with failure for most cases.
In fact, differentiation into retinal progenitor cells from human embryonic stem cells is the greatest achievement made thus far in this field, but the differentiation of retinal progenitor cells into photoreceptor cells failed (differentiation rate of less than 0.01%) (Lamba, Proc. Natl. Acad. Sci. USA, 2006; 103: 12769-74). One report held that human embryonic stem cells were successfully induced to differentiate into photoreceptor cells, but the method used therein requires more than 200 days in total for the differentiation, with a differentiation rate of as low as 8%, and thus is impossible to apply to the clinical treatment of blindness (Osakada et al., Nat. Biotechnol., 2008; 26: 215-24).